Breast cancer risk in relation to the interval between menopause and starting hormone therapy

Abstract

Background: Although breast cancer risk is greater in users of estrogen-progestin than estrogen-only formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence.

Methods: A total of 1,129,025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided.

Results: During 4.05 million woman-years of follow-up, 15,759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (P(heterogeneity) < .001, for both estrogen-only and estrogen-progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen-progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively). At 50-59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen-progestin formulations who began use less than 5 years after menopause.

Conclusions: There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen-progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later.

Figure 1

Risk of breast cancer, by use of hormone therapy. Relative risks (RRs) were calculated, taking never users of hormone therapy as the comparison group (RR = 1.0), stratifying by age, and adjusting by region of residence, socioeconomic status, age at menopause, body mass index, age at birth of first child, parity, and alcohol consumption. Relative risks (and their floated confidence intervals [fCIs]) are represented by squares and lines, with the area of every square being inversely proportional to the variance of the logarithm of the relative risk. This presentation thus provides an appropriate indication of the amount of statistical information involved. The dotted line represents the relative risk for all current users compared with never users. * = Estimated average total duration of use of hormone therapy at the time of diagnosis of breast cancer. †= Cases denote women with breast cancer.

Figure 2

Risk of breast cancer, in current users and in past users by time since stopping hormone therapy. Relative risks (RRs) were calculated by taking never users of hormone therapy as the comparison group (RR = 1.0), stratifying by age, and adjusting by region of residence, socioeconomic status, age at menopause, body mass index, age at birth of first child, parity, and alcohol consumption. Relative risks (and their floated confidence intervals [fCIs]) are represented by circles and lines. The dotted line represents the relative risk for all never users. It should be noted that, for current users, time since last use is effectively zero.

Figure 3

Risk of breast cancer in current users of hormone therapy by tumor characteristics. Relative risks (RRs) were calculated by taking never users of hormone therapy as the comparison group (RR = 1.0), stratifying by age, and adjusting by region of residence, socioeconomic status, age at menopause, body mass index, age at birth of first child, parity, and alcohol consumption. Relative risks (and their confidence intervals [CIs]) are represented by squares and lines, with the area of every square being inversely proportional to the variance of the logarithm of the relative risk. † = Cases denote women with breast cancer.

Figure 4

Risk of breast cancer in current users of estrogen-only and estrogen–progestin hormone therapy by the timing of first use and total duration of use. Relative risks (RRs) were calculated by taking never users of hormone therapy as the comparison group (RR = 1.0, 95% CI = 0.97 to 1.03), stratifying by age, and adjusting by region of residence, socioeconomic status, age at menopause, body mass index, age at birth of first child, parity, and alcohol consumption. Relative risks (and their floated confidence intervals [fCIs]) are represented by squares and lines, with the area of every square is inversely proportional to the variance of the logarithm of the relative risk. * = Estimated average total duration of use of hormone therapy at the time of diagnosis of breast cancer. The dotted line represents the overall relative risk estimates for current users of each type of hormone therapy. † = Cases denote women with breast cancer.

Figure 5

Standardized incidence rates for breast cancer in current users of hormone therapy by the type of hormone therapy used and women’s body mass index. Standardized incidence rates per 100 women aged 50–59 years per year were calculated by taking never users of hormone therapy as the standard and standardizing by age, region of residence, socioeconomic status, age at menopause, age at birth of first child, parity, and alcohol consumption. It should be noted that incidence rates are plotted against the mean body mass index within each subgroup. 95% confidence intervals are shown (error bars).

Figure 6

Risk of breast cancer in current users estrogen-only and estrogen–progestin hormone therapy, by the timing of first use and women's body mass index. Relative risks (RRs) were calculated by taking never users of hormone therapy as the comparison group (RR = 1.0), stratifying by age, and adjusting by region of residence, socioeconomic status, age at menopause, body mass index, age at birth of first child, parity, and alcohol consumption. Relative risks (and their floated confidence intervals [fCIs]) are represented by squares and lines, with the area of every square is inversely proportional to the variance of the logarithm of the relative risk. * = Estimated average total duration of use of hormone therapy at the time of diagnosis of breast cancer. The dotted line represents the overall relative risk estimates for current users of each type of hormone therapy. † = Cases denote women with breast cancer.